Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes

Helmrich, Anne; Stout-Weider, Karen; Hermann, K.; Schröck, Evelin; Heiden, Thomas

doi:10.1101/gr.5335506

Cited by 100 publications

(110 citation statements)

References 39 publications

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“…The minimal deletion region contains nearly twice the number of peaks per kilobase (1 peak per 29 kb) than the proximal segment of FHIT (1 peak every 56 kb) but nearly the same number of peaks per kilobase as the distal segment of FHIT (1 peak per 31 kb). These values are similar to the average incidence of flexibility peaks reported for both CFS and nonfragile regions of the human genome (1 peak per 24-32 kb) (32). No peaks were found to lie at predicted deletion boundaries, consistent with previously published studies that report that cancer-derived cell lines with FHIT/FRA3B deletions do not coincide with flexibility peaks (28).…”

Section: Aph-induced Deletions Within Fhit Resemble Those Found In Casupporting

confidence: 80%

Replication stress induces tumor-like microdeletions in FHIT /FRA3B

Durkin

Ragland

Arlt

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

112

109

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Common fragile sites (CFSs) are loci that preferentially exhibit metaphase chromosome gaps and breaks after partial inhibition of DNA synthesis. The fragile site FRA3B, which lies within the FHIT tumorsuppressor gene, is a site of frequent heterozygous and homozygous deletions in many cancer cells and precancerous lesions. The great majority of FHIT and other CFS-associated gene rearrangements in tumors are submicroscopic, intralocus deletions of hundreds of kilobases that often result in inactivation of associated genes. Although CFS instability leads to chromosome gaps and breaks and translocations, there has been no direct evidence showing that CFS instability or replication stress can generate large submicroscopic deletions of the type seen in cancer cells. Here, we have produced FHIT/FRA3B deletions closely resembling those in tumors by exposing humanmouse chromosome 3 somatic hybrid cells to aphidicolin-mediated replication stress. Clonal cell populations were analyzed for deletions by using PCR, array comparative genomic hybridization (aCGH), and FISH. Thirteen percent to 23% of clones exhibited submicroscopic FHIT deletions spanning Ϸ200 -600 kb within FRA3B. Chromosomes with FRA3B deletions exhibited significantly decreased fragility of this locus, with a 2-to 12-fold reduction in metaphase gaps and breaks compared with controls. Sequence analysis showed no regions of homology at breakpoints and suggests involvement of NHEJ in generating the deletions. Our results demonstrate that replication stress induces a remarkably high frequency of tumor-like microdeletions that reduce fragility at a CFS in cultured cells and suggests that similar conditions during tumor formation lead to intralocus deletion and inactivation of genes at CFSs and perhaps elsewhere in the genome.fragile site ͉ genome instability ͉ replication stress C ommon fragile sites (CFSs) are regions of the genome that are particularly susceptible to forming gaps and breaks on metaphase chromosomes under conditions of replication stress induced by certain inhibitors of DNA synthesis, particularly the polymeraseinhibiting drug, aphidicolin (APH) (1, 2). The ATR-dependent DNA damage checkpoint has been shown to be centrally involved in maintenance of CFS stability, leading to the model that CFS lesions result from stalled replication at these sites (3-6).In addition to cytogenetic ''expression'' of CFS gaps and breaks on metaphase chromosomes, CFSs exhibit a number of additional characteristics of unstable DNA in cultured cells. After induction with APH, the majority of CFS breaks display sister chromatid exchanges (SCEs) (7). Chromosome breakage at CFSs can lead to translocations and gross chromosome terminal deletions after APH treatment in somatic cell hybrid systems in which there is no negative selection for loss of genes distal to the CFS (8, 9). CFSs are also preferred sites of integration for transfected DNA in cells pretreated with APH (10-12) and have been implicated in breakage leading to intrachromosomal gene amplification events in ...

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Section: Aph-induced Deletions Within Fhit Resemble Those Found In Casupporting

confidence: 80%

Replication stress induces tumor-like microdeletions in FHIT /FRA3B

Durkin

Ragland

Arlt

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

112

109

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“…For instance, human and mouse AKNA genes are respectively located within fragile chromosome 9 FRA9E and 4 FRA4C2 regions, and these loci are known to be frequently altered in inflammatory diseases and cancer [24,58]. This suggests that, in humans, AKNA gene lesions could be a determining risk factor for how neutrophilmediated inflammatory reactions resolve into acute syndromes and/or neoplastic disorders [59].…”

Section: Discussionmentioning

confidence: 99%

“…The recent finding that single nucleotide polymorphisms (SNP) within the human AKNA AT-hook domain increase the risk of cervical cancer [23] lends support to this concept. Furthermore, mouse Fra4C2 on chromosome 4 shares a CFS of synteny with the human FRA9E region [24], which underscores the evolutionary resemblance of conserved chromosome instability and suggests potential biological parallels between them. Based on this reasoning, we engineered two independent gene-targeting mouse models to assess in vivo the physiological significance of AKNA gene expression.…”

Section: Introductionmentioning

confidence: 95%

Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice

Ortiz‐Quintero

Rangel

et al. 2011

Cell Res

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Gene expression can be regulated by chromatin modifiers, transcription factors and proteins that modulate DNA architecture. Among the latter, AT-hook transcription factors have emerged as multifaceted regulators that can activate or repress broad A/T-rich gene networks. Thus, alterations of AT-hook genes could affect the transcription of multiple genes causing global cell dysfunction. Here we report that targeted deletions of mouse AKNA, a hypothetical AT-hook-like transcription factor, sensitize mice to pathogen-induced inflammation and cause sudden neonatal death. Compared with wild-type littermates, AKNA KO mice appeared weak, failed to thrive and most died by postnatal day 10. Systemic inflammation, predominantly in the lungs, was accompanied by enhanced leukocyte infiltration and alveolar destruction. Cytologic, immunohistochemical and molecular analyses revealed CD11b + Gr1 + neutrophils as major tissue infiltrators, neutrophilic granule protein, cathelin-related antimicrobial peptide and S100A8/9 as neutrophil-specific chemoattracting factors, interleukin-1β and interferon-γ as proinflammatory mediators, and matrix metalloprotease 9 as a plausible proteolytic trigger of alveolar damage. AKNA KO bone marrow transplants in wildtype recipients reproduced the severe pathogen-induced reactions and confirmed the involvement of neutrophils in acute inflammation. Moreover, promoter/reporter experiments showed that AKNA could act as a gene repressor. Our results support the concept of coordinated pathway-specific gene regulation functions modulating the intensity of inflammatory responses, reveal neutrophils as prominent mediators of acute inflammation and suggest mechanisms underlying the triggering of acute and potentially fatal immune reactions.

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“…Cependant, des études à haut débit n'ont pas confirmé la richesse particulière des SFC en séquences capables de former des structures secondaires [8].…”

Section: Réplication Complèteunclassified